“Sticky” Conundrums in the Endothelin System: Unique Binding Characteristics of Receptor Agonists and Antagonists

Wu-Wong, Jinshyun R.

doi:10.1007/978-3-662-11672-2_4

Cited by 3 publications

(6 citation statements)

References 53 publications

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“…The tenacious binding of ETs to their receptors (mainly ET-1 and ET-3), may explain the long-lasting vasoconstrictor effects of these peptides. Some hypotheses, such as a peculiar interaction between ET receptors and G proteins, disulfide interchange in the ET receptor-ligand complex and a continuous ET receptor externalization, have been proposed to explain the stability of the ligand-receptor complex [1,42]. These binding properties of ET1 may be of practical significance, as will be discussed below.…”

Section: Endothelin Receptorsmentioning

confidence: 99%

“…Due to the tenacious binding of ET-1 and reversible binding of antagonists, the potency of an antagonist to inhibit ET-1 binding inversely depends on the length of the incubation time (in vitro, the potency of an antagonist decreases during prolonged incubation with ET-1; ref. 42). However, and as it has been extensively described in the literature, ET receptor antagonists are efficacious in vivo, specially in chronic situations.…”

Section: Endothelin Antagonistsmentioning

confidence: 99%

“…Although ET-1 binding is "irreversible", free or unoccupied ET-1 receptors will recycle back to the membrane surface and are free to bind ET-1 antagonists, which are continuously present with chronic administration in vivo [42]. Another factor that may interfere with the actions of ET-1 antagonists in vivo, and that should be taken into consideration when comparing their potencies, is the degree of binding to serum albumin, considering their lipophilic acid nature, a structural characteristic of almost all ET-1 antagonists [42].…”

Section: Endothelin Antagonistsmentioning

confidence: 99%

“…On the other hand, the observation that changes in plasma ET-1 levels can be detected and have been described in the above mentioned cardiovascular diseases -atherosclerosis, myocardial infarction, pulmonary hypertension, heart / renal failureargues in favour of the use of plasma ET-1 levels as a marker of activation of the ET system. Furthermore, considering that ET-1 binding to its receptors is practically irreversible, and that the Kd values are in the picomolar range, it is possible that small changes in plasma levels do have pathological significance, even though it rarely rises to the nanomolar range [42].…”

Section: Role Of Ets In Cardiovascular Diseasesmentioning

confidence: 99%

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Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Tostes

Muscará

2005

CDTCHD

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Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties which have been implicated in the pathophysiology of a number of cardiovascular diseases. ET-1 effects are mediated through activation of the G-protein-coupled ETA and ETB receptors, which are found in a variety of cells including endothelial, vascular smooth muscle and mesangial cells. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. The development of a range of peptidic and nonpeptidic ET-1 receptor antagonists represents an exciting breakthrough in cardiovascular therapeutics. Endothelin antagonists improve endothelium-dependent relaxation and ameliorate vascular and cardiac hypertrophy as well as glomerulosclerosis; interestingly, these beneficial effects seem to occur independently of their capacity to lower blood pressure. The comparison between selective ETA and combined ETA/ETB antagonists in experimental models of cardiovascular diseases reveals no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. In the case of salt-sensitive hypertension, ETA receptor blockade leads to the prevention of vascular hypertrophy and renal function improvement, being likely that these effects are also mediated by ETB receptors based on the fact that the concomitant blockade of ETB receptors prevents the beneficial effects of ETA antagonists. As a whole, the available data indicate that the use of ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damage; however, the comparative efficacy of selective ETA vs. dual ETA/ETB blockade to prevent target organ injuries in humans still remains to be investigated.

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Section: Endothelin Receptorsmentioning

confidence: 99%

Section: Endothelin Antagonistsmentioning

confidence: 99%

Section: Endothelin Antagonistsmentioning

confidence: 99%

Section: Role Of Ets In Cardiovascular Diseasesmentioning

confidence: 99%

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Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Tostes

Muscará

2005

CDTCHD

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“…The ET A receptor is the predominant subtype in adult cardiac myocytes, and a mixed population of ET A and ET B receptors has been described in cardiac fibroblasts and in endocardial endothelial cells [21][22][23]. Renal ET B receptors represent the major population of ET receptors (70 % of the receptors in both cortex and medulla), localizing both to endothelial cells and non-vascular tissues (tubules and collecting ducts) [31][32][33]. ET A receptors are localized to vascular smooth muscle of arteries and veins as well as intra-renal resistance vessels and, probably due to the high density of ET receptors, the renal vasculature is highly sensitive to the pre-and post-glomerular vasoconstrictor actions of ET-1 [18,24,25].…”

Section: Et Receptorsmentioning

confidence: 99%

Endothelin, sex and hypertension

et al. 2007

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The ETs (endothelins) comprise a family of three 21-amino-acid peptides (ET-1, ET-2 and ET-3) and 31-amino-acid ETs (ET-1(1-31), ET-2(1-31) and ET-3(1-31)). ET-1 is synthesized from a biologically inactive precursor, big ET-1, by ECEs (ET-converting enzymes). The actions of ET-1 are mediated through activation of the G-protein-coupled ET(A) and ET(B) receptors, which are found in a variety of cells in the cardiovascular and renal systems. ET-1 has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties, which have been implicated in the pathophysiology of a number of cardiovascular diseases. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. Sex differences are observed in many aspects of mammalian cardiovascular function and pathology. Hypertension, as well as other cardiovascular diseases, is more common in men than in women of similar age. In experimental models of hypertension, males develop an earlier and more severe form of hypertension than do females. Although the reasons for these differences are not well established, the effects of gonadal hormones on arterial, neural and renal mechanisms that control blood pressure are considered contributing factors. Sex differences in the ET-1 pathway, with males displaying higher ET-1 levels, greater ET-1-mediated vasoconstrictor and enhanced pressor responses in comparison with females, are addressed in the present review. Sex-associated differences in the number and function of ET(B) receptors appear to be particularly important in the specific characteristics of hypertension between females and males. Although the gonadal hormones modulate some of the differences in the ET pathway in the cardiovascular system, a better understanding of the exact mechanisms involved in sex-related differences in this peptidergic system is needed. With further insights into these differences, we may learn that men and women could require different antihypertensive regimens.

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Using Receptor Antagonists in Binding Studies to Characterize a Mammalian Endothelin Receptor

Wu-Wong

Peptide Research Protocols

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“Sticky” Conundrums in the Endothelin System: Unique Binding Characteristics of Receptor Agonists and Antagonists

Cited by 3 publications

References 53 publications

Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Endothelin, sex and hypertension

Using Receptor Antagonists in Binding Studies to Characterize a Mammalian Endothelin Receptor

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